Minimally invasive access for renal nerve ablation

ABSTRACT

An elongated flexible medical device is inserted into a patient&#39;s body via a natural orifice, and advanced through the natural orifice to a location proximate innervated tissue that influences renal sympathetic nerve activity. The medical device can be advanced into a body organ and to a location within the organ proximate the innervated tissue. The organ may comprise an organ of the gastrointestinal tract or urinary tract. The medical device may be advanced through and beyond an access hole in a wall of the organ, and situated at a location proximate the innervated tissue. One or both of imaging and ablation energy is delivered from a distal end of the medical device to the innervated tissue. Innervated renal tissue can be ablated using various forms of energy, including RF energy, ultrasound energy, optical energy, and thermal energy.

RELATED PATENT DOCUMENTS

This application claims the benefit of Provisional Patent ApplicationSer. Nos. 61/414,299 filed Nov. 16, 2010 and 61/491,731 filed May 31,2011, to which priority is claimed pursuant to 35 U.S.C. §119(e) andwhich are hereby incorporated herein by reference.

SUMMARY

Devices, systems, and methods of the disclosure are directed to ablatingtarget tissue of the body, imaging target tissue of the body, and bothimaging and ablating target tissue of the body. Devices, systems, andmethods of the disclosure are directed to ablating and/or imaging targettissue of the body using a medical device introduced into the body via anatural orifice or a minimally invasive access path. Embodiments aredirected to modifying renal sympathetic nerve activity using one or acombination of ablation apparatuses and methodologies. Embodiments aredirected to imaging innervated tissue that influences renal sympatheticnerve activity using an imaging arrangement, and ablating the innervatedtissue using an ablation apparatus, wherein at least one of the imagingand ablation apparatuses is configured for introduction into the bodyvia a natural orifice or a minimally invasive access path.

Various embodiments of the disclosure are directed to methods involvinginserting an elongated flexible medical device into a patient's body viaa natural orifice, advancing the medical device through the naturalorifice and to a location proximate innervated tissue that influencesrenal sympathetic nerve activity, and delivering energy from a distalend of the medical device to the innervated tissue. Inserting themedical device into the patient's body may involve inserting the medicaldevice into an organ of the patient's body and to a location within theorgan proximate the innervated tissue. The organ may comprise an organof the patient's gastrointestinal tract or urinary tract. Inserting themedical device into the patient's body may involve advancing the medicaldevice through an access hole in a wall of the organ, and advancing themedical device beyond the access hole and to a location proximate theinnervated tissue.

According to some embodiments, the medical device is advanced through atleast a portion of the patient's digestive system via an uppergastrointestinal access path. In other embodiments, the medical deviceis advanced through at least a portion of the patient's digestive systemvia a lower gastrointestinal access path. In further embodiments, themedical device is advanced through at least a portion of a ureter of thepatient accessed via the patient's bladder. The innervated tissue can beablated using various forms of energy, including RF energy, ultrasoundenergy, optical energy, and thermal energy.

In accordance with various embodiments, apparatuses of the disclosureinclude an elongated flexible medical device configured for insertioninto a patient's body via a natural orifice. The medical devicepreferably has a length sufficient for advancement between the naturalorifice and a location at or proximate innervated tissue that influencesrenal sympathetic nerve activity via an internal body pathway, such asthe gastrointestinal tract or urinary tract of the patient. An energydelivery device is provided at a distal end of the medical device andconfigured to communicate energy to the location at or proximate theinnervated tissue. The energy delivery device may include aradiofrequency ablation device, an ultrasound ablation device, anoptical ablation device, or a thermal ablation device.

The medical device may be configured for insertion into an organ of thepatient's body via the natural orifice. The medical device may beconfigured for extra-organ deployment via an access hole in the organ.The medical device may be configured for advancement through at least aportion of the patient's digestive system via an upper gastrointestinalaccess path or a lower gastrointestinal access path. In someembodiments, the medical device may be configured for advancementthrough at least a portion of a ureter of the patient accessed via thepatient's bladder.

These and other features can be understood in view of the followingdetailed discussion and the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of a right kidney and renal vasculatureincluding a renal artery branching laterally from the abdominal aorta;

FIGS. 2A and 2B illustrate sympathetic innervation of the renal artery;

FIG. 3A illustrates various tissue layers of the wall of the renalartery;

FIGS. 3B and 3C illustrate a portion of a renal nerve;

FIG. 4 illustrates a medical system including a medical devicepositioned within an organ, body of tissue, or cavity of the patient'sbody near the renal artery accessed via a natural orifice in accordancewith various embodiments;

FIG. 5 illustrates a medical device positioned within a gastrointestinalorgan of the patient's body near the renal artery accessed via a naturalorifice and an upper gastrointestinal pathway in accordance with variousembodiments;

FIG. 6 illustrates a medical device positioned within a gastrointestinalorgan of the patient's body near the renal artery accessed via a naturalorifice and a lower gastrointestinal pathway in accordance with variousembodiments;

FIG. 7 illustrates a medical device positioned outside of agastrointestinal organ of the patient's body near the renal arteryaccessed via a natural orifice and a lower gastrointestinal pathway inaccordance with various embodiments;

FIGS. 8 and 9 illustrate a medical device positioned within an organ,body of tissue, or cavity of the patient's body near the renal arteryaccessed via a natural orifice and a second medical device positionedwithin the renal artery in accordance with various embodiments;

FIG. 10 illustrates a medical device positioned within an organ of thepatient's body near the renal artery accessed via a natural orifice anda urinary tract pathway, and further illustrates an optional secondmedical device positioned within the renal artery in accordance withvarious embodiments;

FIG. 11 illustrates a medical system including a medical devicepositioned within a blood vessel of the patient's body near the renalartery accessed via a minimally invasive access pathway in accordancewith various embodiments;

FIGS. 12 and 13 illustrate ultrasound energy delivery devices providedat a distal end of a medical device in accordance with variousembodiments;

FIGS. 14 and 15 illustrate optical energy delivery devices provided at adistal end of a medical device in accordance with various embodiments;

FIG. 16 illustrates a thermal energy delivery device provided at adistal end of a medical device in accordance with various embodiments;and

FIG. 17 illustrates a medical system for ablating innervated renaltissue using radiofrequency energy in accordance with variousembodiments.

DESCRIPTION

Embodiments of the disclosure are directed to apparatuses and methodsfor ablating target tissue of the body using at least one of variousforms of energy. Embodiments of the disclosure are directed toapparatuses and methods for imaging target tissue of the body using atleast one of various forms of energy. Embodiments of the disclosure aredirected to apparatuses and methods for both imaging and ablating targettissue of the body using at least one of various forms of energy. One orboth of imaging and ablating target tissue of the body is preferablyperformed by accessing an organ, body of tissue, or a cavity or space ofthe body situated near the target tissue via a natural orifice of thebody. Embodiments of the disclosure are directed to one or both ofimaging and ablating innervated tissue that influences sympathetic renalnerve activity performed by accessing an organ, body of tissue, cavityor space of the body situated near the innervated renal tissue via anatural orifice of the body, such as for control of hypertension.

Various embodiments are directed to apparatuses and methods forutilizing one or more body pathways for accessing target tissue within apatient's body. Suitable body pathways include those that utilize anatural orifice of the body. In some embodiments, a minimally invasivepercutaneous access location of the patient's body is used to gainaccess to a body pathway within the patient. In this context, apercutaneous access location is not considered part of the body pathway,but instead provides access to the body pathway.

Representative non-limiting body pathways include internal pathways thatpass at least partially into, through, or around one or a combination oforgans, tissue bodies, cavities, vessels, ducts, chambers, spacesbetween organs (sometimes filled with fluid), virtual spaces defined byloosely connected interfaces between organs or tissues usually directlyapposed but capable of being separated when deformed or displaced (suchas when fluid is injected or a catheter introduced), space between anabdominal wall and adjacent fascia, intraperitoneal space, andretroperitoneal space, for example. Representative non-limiting organsin the context of various body pathway embodiments include the brain,kidney, heart, liver, nerves, small intestine, colon, lungs, bladder andureter, and psoas muscle, among many others. Preferred body pathways arethose that originate from a natural orifice of the body.

According to various embodiments, an endoscope or other medical deviceis placed in the gastrointestinal tract, such as through the mouth ornose, through the esophagus, stomach, and into the small intestine. Atthe duodenum or the jejunum, an imaging device can be placed to aid intreatment of perivascular renal nerves and/or an ablation device can beplaced to ablate the renal nerves. A medical device can be used insidethe intestines, or the intestinal wall can be pierced to gain access tothe nearby renal nerves.

In other embodiments, an endoscopic access through the anus is used toplace an imaging or treatment device in the colon, which passes near therenal nerves. In further embodiments, the hepatic or portal venouscirculation is accessed, such as in a manner similar to a TIPS(transjugular intrahepatic portosystemic shunt) procedure, and used togain access to nearby renal nerves. In some embodiments, renal nerveaccess can be achieved using a trans-hepatic route via the inferior venacava and hepatic vein, similar to a TIPS procedure. In variousembodiments, renal nerve access can be achieved using a body pathwaythat includes the inferior vena cava, hepatic vein, liver, andintraperitoneum. According to other embodiments, the ureter(s) areaccessed by a ureteroscope or other catheter system in a manner similarto ureteral stenting or kidney stone removal, and used to gain access tonearby renal nerves.

Combinations of various access approaches and/or conventional approachescan be used to provide improved location, imaging, and focusing ofenergy sources to provide improved renal nerve ablation with less injuryto the renal artery. For example, a large or distributed electrode inthe small intestine or colon, and a smaller electrode in the renalartery or renal vein, can be used for a bipolar RF ablation procedurewith improved treatment area localization. Other body cavities, vessels,chambers, organs, or potential spaces can be used to access the renalnerves. Other forms of energy can be delivered for one or both ofimaging and ablating innervated renal tissue.

Various embodiments of the disclosure are directed to apparatuses andmethods for renal denervation for treating hypertension. Hypertension isa chronic medical condition in which the blood pressure is elevated.Persistent hypertension is a significant risk factor associated with avariety of adverse medical conditions, including heart attacks, heartfailure, arterial aneurysms, and strokes. Persistent hypertension is aleading cause of chronic renal failure. Hyperactivity of the sympatheticnervous system serving the kidneys is associated with hypertension andits progression. Deactivation of nerves in the kidneys via renaldenervation can reduce blood pressure, and may be a viable treatmentoption for many patients with hypertension who do not respond toconventional drugs.

The kidneys are instrumental in a number of body processes, includingblood filtration, regulation of fluid balance, blood pressure control,electrolyte balance, and hormone production. One primary function of thekidneys is to remove toxins, mineral salts, and water from the blood toform urine. The kidneys receive about 20-25% of cardiac output throughthe renal arteries that branch left and right from the abdominal aorta,entering each kidney at the concave surface of the kidneys, the renalhilum.

Blood flows into the kidneys through the renal artery and the afferentarteriole, entering the filtration portion of the kidney, the renalcorpuscle. The renal corpuscle is composed of the glomerulus, a thicketof capillaries, surrounded by a fluid-filled, cup-like sac calledBowman's capsule. Solutes in the blood are filtered through the verythin capillary walls of the glomerulus due to the pressure gradient thatexists between the blood in the capillaries and the fluid in theBowman's capsule. The pressure gradient is controlled by the contractionor dilation of the arterioles. After filtration occurs, the filteredblood moves through the efferent arteriole and the peritubularcapillaries, converging in the interlobular veins, and finally exitingthe kidney through the renal vein.

Particles and fluid filtered from the blood move from the Bowman'scapsule through a number of tubules to a collecting duct. Urine isformed in the collecting duct and then exits through the ureter andbladder. The tubules are surrounded by the peritubular capillaries(containing the filtered blood). As the filtrate moves through thetubules and toward the collecting duct, nutrients, water, andelectrolytes, such as sodium and chloride, are reabsorbed into theblood.

The kidneys are innervated by the renal plexus which emanates primarilyfrom the aorticorenal ganglion. Renal ganglia are formed by the nervesof the renal plexus as the nerves follow along the course of the renalartery and into the kidney. The renal nerves are part of the autonomicnervous system which includes sympathetic and parasympatheticcomponents. The sympathetic nervous system is known to be the systemthat provides the bodies “fight or flight” response, whereas theparasympathetic nervous system provides the “rest and digest” response.Stimulation of sympathetic nerve activity triggers the sympatheticresponse which causes the kidneys to increase production of hormonesthat increase vasoconstriction and fluid retention. This process isreferred to as the renin-angiotensin-aldosterone-system (RAAS) responseto increased renal sympathetic nerve activity.

In response to a reduction in blood volume, the kidneys secrete renin,which stimulates the production of angiotensin. Angiotensin causes bloodvessels to constrict, resulting in increased blood pressure, and alsostimulates the secretion of the hormone aldosterone from the adrenalcortex. Aldosterone causes the tubules of the kidneys to increase thereabsorption of sodium and water, which increases the volume of fluid inthe body and blood pressure.

Congestive heart failure (CHF) is a condition that has been linked tokidney function. CHF occurs when the heart is unable to pump bloodeffectively throughout the body. When blood flow drops, renal functiondegrades because of insufficient perfusion of the blood within the renalcorpuscles. The decreased blood flow to the kidneys triggers an increasein sympathetic nervous system activity (i.e., the RAAS becomes tooactive) that causes the kidneys to secrete hormones that increase fluidretention and vasorestriction. Fluid retention and vasorestriction inturn increases the peripheral resistance of the circulatory system,placing an even greater load on the heart, which diminishes blood flowfurther. If the deterioration in cardiac and renal functioningcontinues, eventually the body becomes overwhelmed, and an episode ofheart failure decompensation occurs, often leading to hospitalization ofthe patient.

FIG. 1 is an illustration of a right kidney 10 and renal vasculatureincluding a renal artery 12 branching laterally from the abdominal aorta20. In FIG. 1, only the right kidney 10 is shown for purposes ofsimplicity of explanation, but reference will be made herein to bothright and left kidneys and associated renal vasculature and nervoussystem structures, all of which are contemplated within the context ofembodiments of the disclosure. The renal artery 12 is purposefully shownto be disproportionately larger than the right kidney 10 and abdominalaorta 20 in order to facilitate discussion of various features andembodiments of the present disclosure.

The right and left kidneys are supplied with blood from the right andleft renal arteries that branch from respective right and left lateralsurfaces of the abdominal aorta 20. Each of the right and left renalarteries is directed across the crus of the diaphragm, so as to formnearly a right angle with the abdominal aorta 20. The right and leftrenal arteries extend generally from the abdominal aorta 20 torespective renal sinuses proximate the hilum 17 of the kidneys, andbranch into segmental arteries and then interlobular arteries within thekidney 10. The interlobular arteries radiate outward, penetrating therenal capsule and extending through the renal columns between the renalpyramids. Typically, the kidneys receive about 20% of total cardiacoutput which, for normal persons, represents about 1200 mL of blood flowthrough the kidneys per minute.

The primary function of the kidneys is to maintain water and electrolytebalance for the body by controlling the production and concentration ofurine. In producing urine, the kidneys excrete wastes such as urea andammonium. The kidneys also control reabsorption of glucose and aminoacids, and are important in the production of hormones including vitaminD, renin and erythropoietin.

An important secondary function of the kidneys is to control metabolichomeostasis of the body. Controlling hemostatic functions includeregulating electrolytes, acid-base balance, and blood pressure. Forexample, the kidneys are responsible for regulating blood volume andpressure by adjusting volume of water lost in the urine and releasingerythropoietin and renin, for example. The kidneys also regulate plasmaion concentrations (e.g., sodium, potassium, chloride ions, and calciumion levels) by controlling the quantities lost in the urine and thesynthesis of calcitrol. Other hemostatic functions controlled by thekidneys include stabilizing blood pH by controlling loss of hydrogen andbicarbonate ions in the urine, conserving valuable nutrients bypreventing their excretion, and assisting the liver with detoxification.

Also shown in FIG. 1 is the right suprarenal gland 11, commonly referredto as the right adrenal gland. The suprarenal gland 11 is a star-shapedendocrine gland that rests on top of the kidney 10. The primary functionof the suprarenal glands (left and right) is to regulate the stressresponse of the body through the synthesis of corticosteroids andcatecholamines, including cortisol and adrenaline (epinephrine),respectively. Encompassing the kidneys 10, suprarenal glands 11, renalvessels 12, and adjacent perirenal fat is the renal fascia, e.g.,Gerota's fascia, (not shown), which is a fascial pouch derived fromextraperitoneal connective tissue.

The autonomic nervous system of the body controls involuntary actions ofthe smooth muscles in blood vessels, the digestive system, heart, andglands. The autonomic nervous system is divided into the sympatheticnervous system and the parasympathetic nervous system. In general terms,the parasympathetic nervous system prepares the body for rest bylowering heart rate, lowering blood pressure, and stimulating digestion.The sympathetic nervous system effectuates the body's fight-or-flightresponse by increasing heart rate, increasing blood pressure, andincreasing metabolism.

In the autonomic nervous system, fibers originating from the centralnervous system and extending to the various ganglia are referred to aspreganglionic fibers, while those extending from the ganglia to theeffector organ are referred to as postganglionic fibers. Activation ofthe sympathetic nervous system is effected through the release ofadrenaline (epinephrine) and to a lesser extent norepinephrine from thesuprarenal glands 11. This release of adrenaline is triggered by theneurotransmitter acetylcholine released from preganglionic sympatheticnerves.

The kidneys and ureters (not shown) are innervated by the renal nerves14. FIGS. 1 and 2A-2B illustrate sympathetic innervation of the renalvasculature, primarily innervation of the renal artery 12. The primaryfunctions of sympathetic innervation of the renal vasculature includeregulation of renal blood flow and pressure, stimulation of reninrelease, and direct stimulation of water and sodium ion reabsorption.

Most of the nerves innervating the renal vasculature are sympatheticpostganglionic fibers arising from the superior mesenteric ganglion 26.The renal nerves 14 extend generally axially along the renal arteries12, enter the kidneys 10 at the hilum 17, follow the branches of therenal arteries 12 within the kidney 10, and extend to individualnephrons. Other renal ganglia, such as the renal ganglia 24, superiormesenteric ganglion 26, the left and right aorticorenal ganglia 22, andceliac ganglia 28 also innervate the renal vasculature. The celiacganglion 28 is joined by the greater thoracic splanchnic nerve (greaterTSN). The aorticorenal ganglia 26 is joined by the lesser thoracicsplanchnic nerve (lesser TSN) and innervates the greater part of therenal plexus.

Sympathetic signals to the kidney 10 are communicated via innervatedrenal vasculature that originates primarily at spinal segments T10-T12and L1. Parasympathetic signals originate primarily at spinal segmentsS2-S4 and from the medulla oblongata of the lower brain. Sympatheticnerve traffic travels through the sympathetic trunk ganglia, where somemay synapse, while others synapse at the aorticorenal ganglion 22 (viathe lesser thoracic splanchnic nerve, i.e., lesser TSN) and the renalganglion 24 (via the least thoracic splanchnic nerve, i.e., least TSN).The postsynaptic sympathetic signals then travel along nerves 14 of therenal artery 12 to the kidney 10. Presynaptic parasympathetic signalstravel to sites near the kidney 10 before they synapse on or near thekidney 10.

With particular reference to FIG. 2A, the renal artery 12, as with mostarteries and arterioles, is lined with smooth muscle 34 that controlsthe diameter of the renal artery lumen 13. Smooth muscle, in general, isan involuntary non-striated muscle found within the media layer of largeand small arteries and veins, as well as various organs. The glomeruliof the kidneys, for example, contain a smooth muscle-like cell calledthe mesangial cell. Smooth muscle is fundamentally different fromskeletal muscle and cardiac muscle in terms of structure, function,excitation-contraction coupling, and mechanism of contraction.

Smooth muscle cells can be stimulated to contract or relax by theautonomic nervous system, but can also react on stimuli from neighboringcells and in response to hormones and blood borne electrolytes andagents (e.g., vasodilators or vasoconstrictors). Specialized smoothmuscle cells within the afferent arteriole of the juxtaglomerularapparatus of kidney 10, for example, produces renin which activates theangiotension II system.

The renal nerves 14 innervate the smooth muscle 34 of the renal arterywall 15 and extend lengthwise in a generally axial or longitudinalmanner along the renal artery wall 15. The smooth muscle 34 surroundsthe renal artery circumferentially, and extends lengthwise in adirection generally transverse to the longitudinal orientation of therenal nerves 14, as is depicted in FIG. 2B.

The smooth muscle 34 of the renal artery 12 is under involuntary controlof the autonomic nervous system. An increase in sympathetic activity,for example, tends to contract the smooth muscle 34, which reduces thediameter of the renal artery lumen 13 and decreases blood perfusion. Adecrease in sympathetic activity tends to cause the smooth muscle 34 torelax, resulting in vessel dilation and an increase in the renal arterylumen diameter and blood perfusion. Conversely, increasedparasympathetic activity tends to relax the smooth muscle 34, whiledecreased parasympathetic activity tends to cause smooth musclecontraction.

FIG. 3A shows a segment of a longitudinal cross-section through a renalartery, and illustrates various tissue layers of the wall 15 of therenal artery 12. The innermost layer of the renal artery 12 is theendothelium 30, which is the innermost layer of the intima 32 and issupported by an internal elastic membrane. The endothelium 30 is asingle layer of cells that contacts the blood flowing though the vessellumen 13. Endothelium cells are typically polygonal, oval, or fusiform,and have very distinct round or oval nuclei. Cells of the endothelium 30are involved in several vascular functions, including control of bloodpressure by way of vasoconstriction and vasodilation, blood clotting,and acting as a barrier layer between contents within the lumen 13 andsurrounding tissue, such as the membrane of the intima 32 separating theintima 32 from the media 34, and the adventitia 36. The membrane ormaceration of the intima 32 is a fine, transparent, colorless structurewhich is highly elastic, and commonly has a longitudinal corrugatedpattern.

Adjacent the intima 32 is the media 33, which is the middle layer of therenal artery 12. The media is made up of smooth muscle 34 and elastictissue. The media 33 can be readily identified by its color and by thetransverse arrangement of its fibers. More particularly, the media 33consists principally of bundles of smooth muscle fibers 34 arranged in athin plate-like manner or lamellae and disposed circularly around thearterial wall 15. The outermost layer of the renal artery wall 15 is theadventitia 36, which is made up of connective tissue. The adventitia 36includes fibroblast cells 38 that play an important role in woundhealing.

A perivascular region 37 is shown adjacent and peripheral to theadventitia 36 of the renal artery wall 15. A renal nerve 14 is shownproximate the adventitia 36 and passing through a portion of theperivascular region 37. The renal nerve 14 is shown extendingsubstantially longitudinally along the outer wall 15 of the renal artery12. The main trunk of the renal nerves 14 generally lies in or on theadventitia 36 of the renal artery 12, often passing through theperivascular region 37, with certain branches coursing into the media 33to enervate the renal artery smooth muscle 34.

Embodiments of the disclosure may be implemented to provide varyingdegrees of denervation therapy to innervated renal vasculature. Forexample, embodiments of the disclosure may provide for control of theextent and relative permanency of renal nerve impulse transmissioninterruption achieved by denervation therapy delivered using a treatmentapparatus of the disclosure. The extent and relative permanency of renalnerve injury may be tailored to achieve a desired reduction insympathetic nerve activity (including a partial or complete block) andto achieve a desired degree of permanency (including temporary orirreversible injury).

Returning to FIGS. 3B and 3C, the portion of the renal nerve 14 shown inFIGS. 3B and 3C includes bundles 14 a of nerve fibers 14 b eachcomprising axons or dendrites that originate or terminate on cell bodiesor neurons located in ganglia or on the spinal cord, or in the brain.Supporting tissue structures 14 c of the nerve 14 include theendoneurium (surrounding nerve axon fibers), perineurium (surroundsfiber groups to form a fascicle), and epineurium (binds fascicles intonerves), which serve to separate and support nerve fibers 14 b andbundles 14 a. In particular, the endoneurium, also referred to as theendoneurium tube or tubule, is a layer of delicate connective tissuethat encloses the myelin sheath of a nerve fiber 14 b within afasciculus.

Major components of a neuron include the soma, which is the central partof the neuron that includes the nucleus, cellular extensions calleddendrites, and axons, which are cable-like projections that carry nervesignals. The axon terminal contains synapses, which are specializedstructures where neurotransmitter chemicals are released in order tocommunicate with target tissues. The axons of many neurons of theperipheral nervous system are sheathed in myelin, which is formed by atype of glial cell known as Schwann cells. The myelinating Schwann cellsare wrapped around the axon, leaving the axolemma relatively uncoveredat regularly spaced nodes, called nodes of Ranvier. Myelination of axonsenables an especially rapid mode of electrical impulse propagationcalled saltation.

In some embodiments, a treatment apparatus of the disclosure may beimplemented to deliver denervation therapy that causes transient andreversible injury to renal nerve fibers 14 b. In other embodiments, atreatment apparatus of the disclosure may be implemented to deliverdenervation therapy that causes more severe injury to renal nerve fibers14 b, which may be reversible if the therapy is terminated in a timelymanner. In preferred embodiments, a treatment apparatus of thedisclosure may be implemented to deliver denervation therapy that causessevere and irreversible injury to renal nerve fibers 14 b, resulting inpermanent cessation of renal sympathetic nerve activity. For example, atreatment apparatus may be implemented to deliver a denervation therapythat disrupts nerve fiber morphology to a degree sufficient tophysically separate the endoneurium tube of the nerve fiber 14 b, whichcan prevent regeneration and re-innervation processes.

By way of example, and in accordance with Seddon's classification as isknown in the art, a treatment apparatus of the disclosure may beimplemented to deliver a denervation therapy that interrupts conductionof nerve impulses along the renal nerve fibers 14 b by imparting damageto the renal nerve fibers 14 b consistent with neruapraxia. Neurapraxiadescribes nerve damage in which there is no disruption of the nervefiber 14 b or its sheath. In this case, there is an interruption inconduction of the nerve impulse down the nerve fiber, with recoverytaking place within hours to months without true regeneration, asWallerian degeneration does not occur. Wallerian degeneration refers toa process in which the part of the axon separated from the neuron's cellnucleus degenerates. This process is also known as anterogradedegeneration. Neurapraxia is the mildest form of nerve injury that maybe imparted to renal nerve fibers 14 b by use of a treatment apparatusaccording to embodiments of the disclosure.

A treatment apparatus may be implemented to interrupt conduction ofnerve impulses along the renal nerve fibers 14 b by imparting damage tothe renal nerve fibers consistent with axonotmesis. Axonotmesis involvesloss of the relative continuity of the axon of a nerve fiber and itscovering of myelin, but preservation of the connective tissue frameworkof the nerve fiber. In this case, the encapsulating support tissue 14 cof the nerve fiber 14 b are preserved. Because axonal continuity islost, Wallerian degeneration occurs. Recovery from axonotmesis occursonly through regeneration of the axons, a process requiring time on theorder of several weeks or months. Electrically, the nerve fiber 14 bshows rapid and complete degeneration. Regeneration and re-innervationmay occur as long as the endoneural tubes are intact.

A treatment apparatus may be implemented to interrupt conduction ofnerve impulses along the renal nerve fibers 14 b by imparting damage tothe renal nerve fibers 14 b consistent with neurotmesis. Neurotmesis,according to Seddon's classification, is the most serious nerve injuryin the scheme. In this type of injury, both the nerve fiber 14 b and thenerve sheath are disrupted. While partial recovery may occur, completerecovery is not possible. Neurotmesis involves loss of continuity of theaxon and the encapsulating connective tissue 14 c, resulting in acomplete loss of autonomic function, in the case of renal nerve fibers14 b. If the nerve fiber 14 b has been completely divided, axonalregeneration causes a neuroma to form in the proximal stump.

A more stratified classification of neurotmesis nerve damage may befound by reference to the Sunderland System as is known in the art. TheSunderland System defines five degrees of nerve damage, the first two ofwhich correspond closely with neurapraxia and axonotmesis of Seddon'sclassification. The latter three Sunderland System classificationsdescribe different levels of neurotmesis nerve damage.

The first and second degrees of nerve injury in the Sunderland systemare analogous to Seddon's neurapraxia and axonotmesis, respectively.Third degree nerve injury, according to the Sunderland System, involvesdisruption of the endoneurium, with the epineurium and perineuriumremaining intact. Recovery may range from poor to complete depending onthe degree of intrafascicular fibrosis. A fourth degree nerve injuryinvolves interruption of all neural and supporting elements, with theepineurium remaining intact. The nerve is usually enlarged. Fifth degreenerve injury involves complete transection of the nerve fiber 14 b withloss of continuity.

Referring now to FIG. 4, there is shown a medical system 100 configuredto provide minimally invasive access to innervated tissue thatinfluences renal sympathetic nerve activity, such as renal nerves andganglia. In some embodiments, the medical system 100 can be configuredto provide minimally invasive access to innervated renal tissue via anatural orifice of the body. In various embodiments, for example, themedical system 100 can be configured to provide minimally invasiveaccess to innervated renal tissue via the patient's gastrointestinaltract or urinary tract. In further embodiments, the medical system 100can be configured to provide minimally invasive access to innervatedrenal tissue via an organ or body pathway in proximity to the innervatedrenal tissue.

The medical system 100, according to various embodiments, includes atherapy system 102 coupled to an elongated flexible medical device 130.The medical device 130 is configured to be inserted into the patient'sbody via a natural orifice 106. The medical device 130 preferably has alength sufficient for advancement between the natural orifice 106 and alocation at or proximate innervated tissue that influences renalsympathetic nerve activity via a gastrointestinal tract or a urinarytract of the patient. An energy delivery device 131 is provided at adistal end of the medical device 130.

The energy delivery device 131 is configured to communicate energy tothe location at or proximate the innervated renal tissue. In someembodiments, the energy delivery device 131 is configured to communicateenergy generated by the therapy system 102 sufficient in power orintensity to ablate the innervated renal tissue. In other embodiments,the energy delivery device 131 is configured to communicate energygenerated by an imaging system 120 sufficient to image tissue of thebody, including the innervated renal tissue. In further embodiments, theenergy delivery device 131 is configured to communicate energysufficient to image tissue of the body, including the innervated renaltissue, and energy sufficient to ablate the innervated renal tissuerespectively generated by the therapy system 102 and the imaging system120.

The energy delivery device 131 can be configured to deliver variousforms of energy or a combination of energy forms. In some embodiments,the energy delivery device 131 is configured to deliver radiofrequencyenergy in a bipolar mode using an ablation electrode arrangement at ornear the innervated renal tissue and a return electrode arrangementpositioned within the patient's body. In other embodiments, the energydelivery device 131 is configured to deliver radiofrequency energy in aunipolar mode using an ablation electrode arrangement at or near theinnervated renal tissue and an external return electrode arrangement. Inother embodiments, the energy delivery device 131 is configured todeliver ultrasound energy in one or both of an imaging mode and anablation mode. In further embodiments, the energy delivery device 131 isconfigured to deliver optical energy (e.g., laser) in one or both of animaging mode and an ablation mode. Other forms of energy deliverable bythe energy delivery device 131 are contemplated, such as electricalcurrent, electromagnetic energy of various forms, thermal energy (heator cold), and acoustic energy of various forms for example. In someembodiments, a venom or a neurotoxin can be delivered to ablateinnervated renal tissue.

According to various embodiments, two or more medical devices can beused cooperatively for one or both of ablating and imaging innervatedrenal tissue. For example, and as shown in FIG. 4, medical device 130may be implemented to operate cooperatively with medical device 150,which includes an energy delivery device 151. The energy deliverydevices 131 and 151 may be configured to deliver or respond to the sameor different form of energy. In some embodiments, one of the two medicaldevices 131, 151 may be configured for imaging innervated renal tissuewhile the other of the two medical devices 131, 151 is configured forablating the innervated renal tissue. In other embodiments, each of thetwo medical devices 131, 151 are configured for ablating the innervatedrenal tissue, in which case a third medical device 160 (or an externalimaging system) can be used for imaging the innervated renal tissue,such as by use of an ultrasound energy device 161.

In some embodiments, each of the medical devices 130, 150, and 160 ispositioned within or in proximity to a patient's renal artery 12 via aseparate access path through the body. In other embodiments, two or moreof the medical devices 130, 150, and 160 can be positioned within or inproximity to the patient's renal artery 12 via a body pathway 110 (e.g.,a gastrointestinal organ or urinary vessel) accessed by way of a naturalorifice 106.

By way of example, and in accordance with one embodiment, the energydelivery device 131 of medical device 130 includes an RF electrodearrangement. The medical device 130 is shown positioned within a bodypathway 110, such as within an organ or vessel of the patient'sgastrointestinal or urinary tract accessed via a natural orifice 106, sothat the RF electrode 131 is in proximity to the renal artery 12. Themedical device 150 is shown positioned within the patient's renal artery12 and includes a distal RF electrode 151. It is noted that the medicaldevice 150 may also be positioned within the patient's renal vein orother blood vessel in proximity to the renal artery 12, such as thehepatic portal vein. In this representative example, the medical device150 is coupled to the therapy system 102. The RF electrodes 131 and 151are operated in a bipolar mode for delivering RF energy to tissue of therenal artery 12 sufficient in power to ablate innervated tissue thatinfluences renal sympathetic nerve activity.

FIG. 5 shows delivery of the energy delivery device 131 of medicaldevice 130 through at least a portion of the patient's digestive systemto a location proximate a renal artery 12 via an upper gastrointestinalaccess path in accordance with various embodiments. In therepresentative embodiment shown in FIG. 5, the medical device 130 isinserted into the patient's upper gastrointestinal tract through thepatient's mouth 202. The medical device 130 is advanced through thepatient's esophagus 204, stomach 206, duodenum 208, small intestine 209(jejunum 210 and ileum 212), ascending colon 214 of the large intestine213, and to a proximal location (relative to the direction of medialdevice advancement) within the transverse colon 216. The energy deliverydevice 131 of the medical device 130 is preferably positioned and/ororiented relative to the patient's left renal artery 12 a in a mannerbest suited for imaging and/or ablating innervated tissue of the leftrenal artery 12 a.

After completion of an imaging and/or ablation procedure for the leftrenal artery 12 a, the medical device 130 is advanced through thetransverse colon 216 to a distal location (relative to the direction ofmedial device advancement) in proximity to the patient's right renalartery 12 b. Energy delivery device 131 is preferably positioned and/ororiented relative to the patient's right renal artery 12 b in a mannerbest suited for imaging and/or ablating innervated tissue of the rightrenal artery 12 b. It is noted that anatomical variations betweenpatient's may require positioning of the energy delivery device 131 atlocations of the large intestine 213 other than those shown in FIG. 5.For example, the particular anatomy of a given patient may require thatthe energy delivery device 131 be positioned at or near a distal portionof the ascending colon 214 or proximal portion of the descending colon218, for example.

FIG. 6 shows delivery of the energy delivery device 131 of medicaldevice 130 through at least a portion of the patient's digestive systemto a location proximate a renal artery 12 via a lower gastrointestinalaccess path in accordance with various embodiments. As is shown in FIG.6, the medical device 130 is inserted into the patient's lowergastrointestinal tract through the patient's anus 222. The medicaldevice 130 is advanced through the rectum 220 and into the descendingcolon 218 of the large intestine 213. The energy delivery device 130 canbe positioned at a distal location (relative to the direction of medialdevice advancement) of the descending colon 218 or a proximal locationof the transverse colon 216. One or both of imaging and ablatinginnervated renal tissue of the patient's right renal artery 12 b isperformed, followed by advancement of the energy delivery device 130 toa location of the large intestine 213 in proximity to the patient's leftrenal artery 12 a. As previously discussed, the particular anatomy of agiven patient may require that the energy delivery device 131 bepositioned at or near the distal portion of the transverse colon 216 ora proximal portion of the ascending colon 214.

FIG. 7 shows delivery of the energy delivery device 131 of a medicaldevice 132 to a location proximate the patient's renal artery 12 via alower gastrointestinal access path in accordance with variousembodiments. It is understood that, for purposes of the representativeexample shown in FIG. 7, that the patient's renal artery 12 mayalternatively be accessed via an upper gastrointestinal access path inaccordance with other embodiments. After positioning the energy deliverydevice 131 at a location proximate the patient's right renal artery 12b, for example, the distal tip of the medical device 130 is advancedthrough an access hole 217 created in a wall of a nearby organ orvessel. In the representative example shown in FIG. 7, an access hole217 is created in a wall of the transverse colon 216, through which theenergy delivery device 131 may be advanced to a location on or proximateto the right renal artery 12 b. One or both of imaging and ablatinginnervated renal tissue patient's right renal artery 12 b can bepreformed from an extra-organ or extra-vessel location, such asexternally from the patient's transverse colon 216 is shown in FIG. 7.

The access hole 217 may be created using a variety of techniques. Forexample, the medical device 130 and energy delivery device 131 caninclude a lumen through which a wire having a tissue penetrating tip atits distal end may be advanced and retracted. As another example, theenergy delivery device 131 can incorporate an activatable tissuepiercing feature which can be selectively activated (e.g., extended) anddeactivated (e.g., retracted). By way of further example, the energydelivery device 131 can incorporate a device that generates energysufficient to create the access hole 217, such as a laser device.

FIG. 8 shows an embodiment of a medical system configured for ablatinginnervated tissue of the patient's renal artery 12 in accordance withvarious embodiments. In the illustrative embodiment of FIG. 8, a medicaldevice 130 is advanced through a body pathway 110 of the body to alocation proximate the renal artery 12 via a natural orifice. In thisembodiment, the distal end of the medical device 130 includes an arrayof RF electrodes 132. The body pathway 110 shown in FIG. 8 may be thetransverse colon, the ascending colon, or the descending colon of thepatient, for example. A medical device 150 is shown deployed within alumen 13 of the renal artery 12. The medical device 150 includes anablation electrode 151 provided at a distal end of the medical device150. The array of RF electrodes 132 preferably have a combined ordistributed surface area greater than that of the ablation electrode 151so that high current densities are concentrated at the innervated renaltissue while body pathway 110 remains relatively cool during RFablation.

FIG. 9 shows an embodiment of medical system configured for ablatinginnervated tissue of the patient's renal artery 12 in accordance withvarious embodiments. Similar to the illustrative embodiment of FIG. 8,the medical device 130 shown in FIG. 9 is advanced through a pathway 110of the body to a location proximate the renal artery 12 via naturalorifice. The distal end of the medical device 130 is advanced through awall of the body pathway 110 via an access hole 217. The access hole 217may be created in a manner previously discussed. The distal end of themedical device 113 includes an RF ablation electrode 132, which ispositioned on or proximate the outer wall of the renal artery 12.

FIG. 9 further shows medical device 150 deployed within the lumen 13 ofthe renal artery 12. In this configuration, the distal end of themedical device 150 includes an array of RF electrodes 151. In thisimplementation, high current densities are created near the outer wallof the renal artery 12 while the artery's inner wall remains relativelycool. The implementation shown in FIG. 9 advantageously produces highcurrent densities for ablating renal nerves included within theperivascular space adjacent the renal artery's outer wall, withnegligible thermal injury to the inner wall of the renal artery 12.

FIG. 10 shows deployment of an energy delivery device 131 of the medicaldevice 132 to a location proximate the patient's left renal artery 12 avia a left ureter 160 a of the patient's urinary tract. In thisillustrative embodiment, the medical device 130 is inserted into thepatient's urinary tract via the urethra 164. The medical device 130 isadvanced through the urethra 154, the urinary bladder 162, and the leftureter 160 a to a position proximal to the left renal artery 12 a. Atthis position, the energy delivery device 131 can be used for one orboth of imaging and ablating innervated tissue of the left renal artery12 depending on the device's configuration.

In some embodiments, a second medical device 150 can be advanced to ablood vessel at or proximate to the left renal artery 12 a. Suitableblood vessels include the left renal artery 12 a, the left renal vein,or the hepatic portal vein. In some embodiments, each of the energydelivery devices 131 and 151 can include an RF electrode configured forbipolar RF energy delivery for ablating innervated tissue of the leftrenal artery 12 a. In other embodiments, one of the energy deliverydevices 131 and 151 can be used for imaging, while the other energydelivery devices used for ablating innervated renal tissue. In furtherembodiments, various other forms of imaging and ablation energy can bedelivered using suitable devices, such as ultrasonic, acoustic, andlaser devices.

After imaging and/or innervating tissue of the patient's left renalartery 12 a, the distal tip of the medical device 130 can be retractedfrom the left ureter 160 a and positioned within the urinary bladder 162for insertion into, and advancement through, the patient's right ureter160 b. The procedures and configurations for imaging and/or ablatinginnervated tissue of the patient's left renal artery 12 a are applicableto the patient's right renal artery 12 b.

FIG. 11 shows delivery of an energy delivery device 131 of a medicaldevice 132 to a location proximate the patient's left renal artery 12 avia an access vein in accordance with various embodiments. In thisillustrative embodiment, the access vein to the left renal artery 12 ais represented by the patient's hepatic portal vein 155. In thisillustrative embodiment, the medical device 130 is advanced into thehepatic portal vein 155 via the venous system and a percutaneous accesshole 107. The embodiment shown in FIG. 9 differs from those of previousembodiments in that a natural orifice of the patient is not used fordelivering the medical device 130 to a body location proximate thepatient's left renal artery 12 a. However, it is believed that imagingand/or ablating innervated renal tissue from a location within thehepatic portal vein 155 represents a less invasive access approach whencompared to inserting a device into the patient's femoral artery or vein(or other major blood vessel) or through laparoscopic or open surgicalapproaches.

In some embodiments, as discussed previously, renal nerve access can beachieved using a trans-hepatic route via the inferior vena cava andhepatic vein, similar to a TIPS procedure. In various embodiments, renalnerve access can be achieved using a body pathway that includes theinferior vena cava, hepatic vein, liver, and intraperitoneum.

As discussed previously, various types of energy delivery devices may beused for imaging and/or ablating tissue of the body, such as innervatedrenal tissue that influences renal sympathetic nerve activity. Suitableenergy delivery devices include electrical, electromagnetic, optical,acoustic, and thermal (heat or cryogenic) energy devices, among others.The following representative energy delivery devices may be implementedin one or more medical devices in accordance with embodiments of theinvention, understanding that this listing is a non-exhaustive,non-limiting recitation of suitable energy delivery devices.

With reference to FIGS. 12 and 13, energy delivery devices 231 may beimplemented to include an ultrasound unit 250 configured for denervatingrenal tissue that contributes to renal sympathetic nerve activity inaccordance with various embodiments. In the embodiments shown in FIGS.12 and 13, an emitter 252 of the ultrasound unit 250 includes anacoustic phased array transducer 252 a which comprises a multiplicity ofacoustic elements 252 b. The phased array transducer 252 a shown in FIG.12 extends over a radial segment of the ultrasound unit's circumference,allowing an acoustic energy beam 262 to pass through an aperture 265(e.g., focusing lens arrangement) and impinge on target tissue. Theemitter 252 of the ultrasound unit 250 may be aimed at target tissue byrotating and translating the catheter 251 (i.e., the body of the medicaldevice) or by moving the ultrasound unit 250 relative to the catheter251, either manually or robotically. The ultrasound unit 250 shown inFIG. 12 may be deployed within a body pathway (e.g., organ or vessel)near the renal artery, and may be particularly useful when positionedoutside of an organ or vessel near the outer wall of the renal artery.

In the embodiment shown in FIG. 13, a phased array transducer 252 aextends over all or nearly all of the ultrasound unit's circumference,allowing an acoustic energy beam 262 to pass through an annular aperture265 (e.g., focusing lens arrangement) and impinge on a circular orcylindrical target tissue region. This embodiment of ultrasound unit 250is particularly useful when positioned within the renal artery, forexample, with renal denervation being conducted without having totranslate or rotate the catheter 251 or ultrasound unit 250.

The ultrasound unit 250 preferably has a capability that allows forfocusing of acoustic energy at desired distances so that all or most ofthe perivascular space adjacent the outer wall of the renal artery canbe treated. For example, a preferred focusing arrangement allows for theprojection of ultrasonic energy through a near wall portion of the renalartery (without thermally injuring the near wall portion) which isfocused at perivascular space adjacent a far wall portion of the artery(which is subject to ablation). Such as focusing arrangement reduces oreliminates the need to reposition the ultrasound unit 250 to treat acircumferential section of the renal artery.

A cooling arrangement may be incorporated in the embodiments of FIGS. 12and 13 to ensure that the temperature of inner arterial wall tissue islimited to prevent thermal injury to this tissue. In embodiments thatinclude focused acoustic transducers or transducer arrays, however, suchcooling arrangement may not be required or desired, which can result inintravascular denervation apparatuses of reduced size and complexity.Details of these and other ultrasound denervation therapy apparatusesand methods are described in commonly owned U.S. Patent Publication Ser.No. 20110257523, filed as U.S. patent application Ser. No. 13/086,116 onApr. 13, 2011, which claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/324,164 filed Apr. 14, 2010 and entitled“Focused Ultrasound for Renal Denervation,” all of which areincorporated herein by reference.

FIGS. 14 and 15 show different embodiments of a phototherapy energydelivery device for denervating tissue that contributes to renalsympathetic nerve activity in accordance with various embodiments. Inthe embodiment shown in FIG. 14, an emitter 352 of a phototherapy unit350 includes an aperture 365 through which an optical energy beam 362passes. The aperture 365 may be a void or a material that allows forefficient transmission of the optical energy beam 362 from the emitter352 and out of the phototherapy unit 350. The aperture 365 and emitter352 are situated at a desired location of the phototherapy unit 350, andcan be “aimed” at target tissue by rotating and translating the catheter351 to which the phototherapy unit 350 is attached. The phototherapyunit 350 shown in FIG. 14 may be deployed within a body pathway (e.g.,organ or vessel) near the renal artery, and may be particularly usefulwhen positioned outside of an organ or vessel near the outer wall of therenal artery.

According to some embodiments, the phototherapy unit 350 can be used toablate perivascular renal nerves tissue using a photodynamic therapyapproach. The phototherapy unit 350 can be positioned at anintravascular location within or proximate a renal artery (e.g., renalvein, hepatic portal vein). Alternatively, the phototherapy unit 350 canbe advanced through a natural orifice to a location proximate the outerwall of the renal artery via one or a combination of body pathways. Asecond medical device can be advanced through a natural orifice and bodypathway so that its distal end is positioned at or near the outer wallof the renal artery. Alternatively, the second medical device can beadvanced along an intravascular pathway and positioned at or near theouter wall of the renal artery by way of a perivascular orintra-to-extra-vascular approach. A photosensitizer may be deliveredfrom the distal end of the second medical device and into perivascularspace surrounding the renal artery. The photosensitizer may be excitedby light emitted by the phototherapy unit 350. The excitedphotosensitizer interacts with molecular oxygen within the perivascularspace causing a rapid reaction that destroys nearby biomolecules,including renal nerves, through apoptosis or necrosis.

FIG. 15 shows a phototherapy unit 350 comprising a multiplicity ofapertures 365 and emitters 352. The apertures 365 and emitters 352 arepreferably situated so that their beam patterns 362 collectively impingeon renal artery tissue in a desired pattern, such as a circumferentialor spiral pattern, and at desired target depths in the outer renalartery wall and/or perivascular space adjacent the outer renal arterywall. The circumferential or spiral lesion may either be continuous or asequential and overlapping line of ablated spots. This embodiment of aphototherapy unit 350 is particularly useful when positioned within therenal artery, for example, with renal denervation being conductedwithout having to translate or rotate the catheter 351 or ultrasoundunit 350.

The phototherapy apparatuses depicted in FIGS. 14 and 15 are configuredto optically couple to a laser light source that generates laser lighthaving a desired wavelength and intensity. In some embodiments, thelaser light source is configured to generate a continuous wave (CW)light beam. In other embodiments, the laser light source is configuredto generate pulses of light. For example, the laser light source may beconfigured as an ultrashort or ultrafast laser that produces tightlyfocused pulses of light. Embodiments that utilize a high intensity flashlamp are also contemplated. Details of these and other phototherapydenervation therapy apparatuses and methods are described in commonlyowned U.S. patent publication Ser. No. 20110257641, filed as U.S. patentapplication Ser. No. 13/086,121 on Apr. 13, 2011, which claims thebenefit of U.S. Provisional Patent Application Ser. No. 61/324,163 filedApr. 14, 2010 and entitled “Phototherapy for Renal Denervation,” all ofwhich are incorporated herein by reference.

FIG. 16 shows a thermal energy delivery device for thermally ablatinginnervated tissue that contributes to renal sympathetic nerve activityin accordance with various embodiments. In the embodiment shown in FIG.16, the energy delivery device 410 includes a thermal transfer apparatus420, which may include a cryotube, cryoballoon, or other cryotherapyelement disposed at the distal end of a medical device catheter 430. Theenergy delivery device 410 shown in FIG. 16 is preferably usedcooperatively with one or more other energy delivery devices configuredfor one or both of imaging and ablating innervated renal tissue. The oneor more other energy deliver devices are configured for advancementthrough a pathway of the body (e.g., organ or vessel) to a locationproximate the renal artery 12 via a natural orifice.

In some embodiments, an ultrasound device can be inserted into thepatient's body via a natural orifice and advanced through a pathway ofthe body to a location proximate the renal artery 12 in which thethermal energy delivery device 410 is deployed. The ultrasound devicecan be used for imaging tissue at or proximate the renal artery 12and/or for ablating innervated renal tissue from a location at orproximate the outer wall of the renal artery 12. Rather than being usedfor cryoablation, the thermal energy delivery device 410 can be used tocool the inner renal artery wall and prevent thermal injury thereto. Insome embodiments, the energy delivery device 410 can be controlled tofreeze target tissue of the renal artery 12, and the ultrasound devicecan be controlled to heat the target tissue using a freeze/thaw cyclingprocedure. The ultrasound device (or a laser device) can be used tocreate cavitation bubbles in the target tissue which generate nervedestroying acoustic shock waves when exploding within the target tissue,for example.

In some embodiments, the thermal transfer apparatus 420 includes aballoon arrangement 420 comprising one or more inflation balloons and afluid delivery arrangement 421 configured to transport a thermaltransfer fluid to and from the distal end the medical device catheter430. The fluid delivery arrangement 421 is fluidly coupled to a fluidsource which may be configured to supply a pressurized thermal transferfluid to the balloon arrangement 420.

The fluid delivery arrangement 421 shown in FIG. 16 includes at leasttwo lumens 422 and 424 configured as supply and return lumens forsupplying a cryogen to the thermal transfer apparatus 420 and returningspent cryogen or gas to the proximal end of the catheter 430,respectively. The cryogen may be circulated through the thermal transferapparatus 420 via a hydraulic circuit that includes a cryogen source,supply and return lumens 422, 424, and a cryotherapy element of thethermal transfer apparatus 420 disposed at the distal end of thecatheter 430. The shaft of the catheter 430 is preferably lined with orotherwise incorporates insulation material(s) having appropriate thermaland mechanical characteristics suitable for a selected cryogen.

The fluid delivery arrangement 421 is preferably fluidly coupled to acryogen source which includes a reservoir fluidly coupled to a pump. Acryogen is contained within the reservoir. A variety of cryogens may beemployed, including cold saline or cold saline and ethanol mixture,Freon or other fluorocarbon refrigerants, nitrous oxide, liquidnitrogen, and liquid carbon dioxide, for example.

The thermal transfer apparatus 420 may be a unitary or multi-componentapparatus. In some embodiments, the cryogen, when released inside thethermal transfer apparatus 420, undergoes a phase change that cools thetreatment portion of the thermal transfer apparatus 420 by absorbing thelatent heat of vaporization from the tissue surrounding the thermaltransfer apparatus 420, and by cooling of the vaporized gas as it entersa region of lower pressure inside the thermal transfer apparatus 420(via the Joule-Thomson effect).

As a result of the phase change and the Joule-Thompson effect, heat isextracted from the surroundings of the thermal transfer apparatus 420,thereby cooling the treatment portion of the thermal transfer apparatus420 and renal tissue that is in contact with the treatment portion ofthe thermal transfer apparatus 420. The gas released inside the thermaltransfer apparatus 420 may be exhausted through an exhaust lumen 424provided in the catheter 430. The pressure inside the thermal transferapparatus 420 may be controlled by regulating one or both of a rate atwhich cryogen is delivered and a rate at which the exhaust gas isextracted.

Details of these and other denervation therapy apparatuses and methodsare described hereinbelow and in commonly owned U.S. patent publicationSer. No. 20110270238, filed as U.S. patent application Ser. No.12/980,952 on Dec. 29, 2010, which claims the benefit of U.S.Provisional Patent Application Ser. No. 61/291,476 filed Dec. 31, 2009;U.S. patent publication Ser. No. 20110263921, filed as U.S. patentapplication Ser. No. 12/980,972 on Dec. 29, 2010, which claims thebenefit of U.S. Provisional Patent Application Ser. No. 61/291,480 filedDec. 31, 2009; and U.S. patent publication Ser. No. 20110307034, filedas U.S. patent application Ser. No. 13/157,844 on Jun. 10, 2011, whichclaims the benefit of U.S. Provisional Patent Application Ser. No.61/353,853 filed Jun. 11, 2010, all of which are incorporated herein byreference.

In other embodiments, the medical device shown in FIG. 16 is configuredto supply a treatment agent to a drug delivery element 420 provided atthe distal end of the catheter 430. The drug delivery element 420 mayinclude a weeping balloon or other delivery arrangement configured todeliver a drug to the wall of the renal artery 12. In some embodiments,a drug delivery medical device can be configured for placement at anouter wall of the renal artery via a body pathway accessed through anatural orifice (see, e.g., FIG. 7). A drug or other ablation agent canbe expelled from the drug delivery element 420 and introduced into theperivascular space adjacent the outer wall of the renal artery.

According to various embodiments, the drug delivery element 420 may beconfigured to deliver a pharmacological agent or mixture of agents(e.g., a neurotoxin or venom) to innervated renal tissue. In otherembodiments, the drug delivery element 420 may be configured to deliverbrachytherapy to innervated renal vasculature, such as by exposing therenal artery 12 to radioactive material or seeds (e.g., iodine-125 orpalladium-103 for low dosage rate brachytherapy, iridium-192 for highdose rate brachytherapy).

Details of these and other denervation therapy apparatuses and methodsare described hereinbelow and in commonly owned U.S. patent publicationSer. No. 20110264086, filed as U.S. patent application Ser. No.13/087,163 on Apr. 14, 2011, which claims the benefit of U.S.Provisional Patent Application Ser. No. 61/324,165 filed Apr. 14, 2010,each of which is incorporated herein by reference.

It can be appreciated that the type of agent delivered by the medicaldevice 410 shown in FIG. 16 and/or a separate medical device deployed ata location external of the renal artery 12 via a natural orifice pathwaywill vary in accordance with the particulars of the therapy deliverydevice 420, examples of which include a thermal transfer fluid (hot orcold), a pharmacological agent(s), radioactive material or seeds,electromagnetic energy (e.g., RF, microwave), optical energy (e.g.,laser, white light), or acoustic energy (e.g., ultrasound). In someembodiments, a combination of denervation therapy and/or imagingapparatuses of disparate type or technology can be used together(concurrently or sequentially) to enhance the efficacy of renaldenervation therapy. Combinations of disparate denervation therapyapparatuses may provided for improved therapy outcomes with reducedtissue trauma when compared to renal denervation approaches that employone type of denervation therapy apparatus.

FIG. 17 shows a representative RF renal therapy apparatus 500 inaccordance with various embodiments. The apparatus 500 illustrated inFIG. 17 includes external electrode activation circuitry 520 whichcomprises power control circuitry 522 and timing control circuitry 524.The external electrode activation circuitry 520, which includes an RFgenerator, is coupled to temperature measuring circuitry 528 and may becoupled to an optional impedance sensor 526. The RF generator of theexternal electrode activation circuitry 520 can be coupled to one orboth of medical devices 130 and 150 in various configurations asindicated by the dashed lines in FIG. 17. As shown, the RF generator ofthe external electrode activation circuitry 520 is preferably coupled toeach of the medical devices 130 and 150 in a bipolar configuration. Theelectrode arrangement 131 of medical device 130 can be deployed within abody pathway 110 accessed via a natural orifice or external of the bodypathway via an access hole. In other embodiments, the RF generator ofthe external electrode activation circuitry 520 may include a return padelectrode 530 that is configured to comfortably engage the patient'sback or other portion of the body near the kidneys for operation in aunipolar mode. Radiofrequency energy produced by the RF generator can besupplied to electrode arrangement 131 of the medical device 130, usingthe return pad electrode 530 as a return, thereby obviating the need formedical device 150 positioned within the renal artery 12 (or renalvein). The radiofrequency energy preferably flows through innervatedrenal tissue in accordance with a predetermined activation sequence.

In general, when renal artery tissue temperatures rise above about 113°F. (50° C.), protein is permanently damaged (including those of renalnerve fibers). If heated over about 65° C., collagen denatures andtissue shrinks. If heated over about 65° C. and up to 100° C., cellwalls break and oil separates from water. Above about 100° C., tissuedesiccates.

According to some embodiments, the electrode activation circuitry 520 isconfigured to control activation and deactivation of one or moreelectrodes of the electrode arrangements 131 and/or 151 in accordancewith a predetermined energy delivery protocol and in response to signalsreceived from temperature measuring circuitry 528. The electrodeactivation circuitry 520 controls radiofrequency energy delivered to theelectrode arrangements 131 and/or 151 so as to maintain the currentdensities at a level sufficient to cause heating of the target tissuepreferably to a temperature of at least 55° C.

In some embodiments, one or more temperature sensors are situated at thearrangements 131 and/or 151, and provide for continuous monitoring ofrenal tissue temperatures, and RF generator power is automaticallyadjusted so that the target temperatures are achieved and maintained. Animpedance sensor arrangement 526 may be used to measure and monitorelectrical impedance during RF denervation therapy, and the power andtiming of the RF generator 520 may be moderated based on the impedancemeasurements or a combination of impedance and temperature measurements.

Various embodiments disclosed herein are generally described in thecontext of ablation of perivascular renal nerves for control ofhypertension. It is understood, however, that embodiments of thedisclosure have applicability in other contexts, such as performingablation from within other vessels of the body, including otherarteries, veins, and vasculature (e.g., cardiac and urinary vasculatureand vessels), and other tissues of the body, including various organs.For example, various embodiments may be configured to treat benignprostatic hyperplasia or to diagnose and/or treat a tumor using anappropriate medical device advanced to the treatment site through atleast a portion of a body pathway of a type described hereinabove.

It is to be understood that even though numerous characteristics ofvarious embodiments have been set forth in the foregoing description,together with details of the structure and function of variousembodiments, this detailed description is illustrative only, and changesmay be made in detail, especially in matters of structure andarrangements of parts illustrated by the various embodiments to the fullextent indicated by the broad general meaning of the terms in which theappended claims are expressed.

What is claimed is:
 1. A method, comprising: inserting an elongatedflexible medical device into a patient's body via a natural orifice;wherein the natural orifice includes a urethra; advancing the medicaldevice through the urethra, through the bladder, and through a ureter toa location proximate innervated tissue that influences renal sympatheticnerve activity; and delivering energy from a distal end of the medicaldevice to one or both of image and ablate the innervated tissue.
 2. Themethod of claim 1, wherein delivering energy from the distal end of themedical device comprises delivering energy of sufficient power orintensity to one or both of ablate the innervated tissue and image theinnervated tissue.
 3. The method of claim 1, wherein delivering energyfrom the distal end of the medical device comprises delivering energy ofsufficient power or intensity to selectively image the innervated tissueand ablate the innervated tissue.
 4. The method of claim 1, whereindelivering energy from the distal end of the medical device comprisesdelivering energy of sufficient power or intensity to ablate theinnervated tissue, the method further comprising imaging tissue of orproximate the innervated tissue using an external imaging device tofacilitate ablation of the innervated tissue by the medical device. 5.The method of claim 1, wherein delivering energy from the distal end ofthe medical device comprises ablating the innervated tissue using atleast one of RF energy, ultrasound energy, optical energy, and thermalenergy.
 6. An apparatus, comprising: an elongated flexible medicaldevice configured for insertion into a patient's body via a naturalorifice, the medical device being configured for and having a lengthsufficient for advancement through a urethra, through a bladder, andthrough a ureter to a position adjacent to a renal artery proximateinnervated tissue that influences renal sympathetic nerve activity viaan internal body pathway of the patient; and an energy delivery deviceprovided at a distal end of the medical device and configured tocommunicate energy to the location at or proximate the innervated tissueto one or both of image and ablate the innervated tissue.
 7. Theapparatus of claim 6, wherein the energy delivery device comprises oneor both of an ablation device configured to ablate the innervated tissueand an imaging device configured to image the innervated tissue.
 8. Theapparatus of claim 6, wherein the energy delivery device comprises adevice configured to selectively image the innervated tissue and ablatethe innervated tissue.
 9. The apparatus of claim 6, wherein the energydelivery device comprises at least one of a radiofrequency ablationdevice, an ultrasound ablation device, an optical ablation device, and athermal ablation device.
 10. The apparatus of claim 6, furthercomprising: a second elongated flexible medical device configured forinsertion into the patient's body and having a length sufficient foradvancement to a second location at or proximate innervated tissuerelative to a body access location of the patient; and a second energydevice provided at a distal end of the second medical device.
 11. Theapparatus of claim 10, wherein the energy delivery device comprises anablation device and the second energy delivery device comprises animaging device.
 12. The method of claim 1, wherein advancing the medicaldevice through the natural orifice, through the bladder, and into aureter to a location proximate innervated tissue that influences renalsympathetic nerve activity includes advancing the medical device to aposition adjacent to a renal artery.